The objective continues to be an understanding of the basic biological and biochemical mechanisms for local regulation of adrenergic neurosecretion in the eye. Drugs that alter sympathetic neurotransmitter release in the anterior uvea have potential utility for treatment of glaucoma. We have demonstrated that several types of presynaptic receptors (alpha2 adrenergic, muscarinic cholinergic, dopaminergic, prostaglandin, angiotensin II) and second messenger systems (cAMP, cGMP) modulate norepinephrine release in the rabbit iris-ciliary body in vitro. To determine which of these control mechanisms act at the neuroeffector junctions associated with aqueous humor formation, we will investigate presynaptic regulation of adrenergic neurosecretion in isolated ciliary processes. We will determine whether adaptive changes in presynaptic receptor responsiveness occur as the result of long-term topical in vivo administration of selected receptor agonists. Explant cultures of neurons from the superior cervical ganglia will be utilized to study the cellular and biochemical aspects of presynaptic receptor function, including sites of modulation (calcium channels vs. distal steps in exocytosis), the role of second messengers and correlative effects on protein phosphorylation at release sites. An important goal of these studies is the identification of key regulatory steps in the sympathetic neurosecretory pathway that could serve as targets for new and effective ocular hypotensive drugs.